Tissue Binding versus Plasma Binding of Drugs: General Principles and Pharmacokinetic Consequences

Fichtl, B.; Nieciecki, A von; Walter, K.

doi:10.1016/b978-0-12-013320-8.50006-x

Cited by 79 publications

(70 citation statements)

References 180 publications

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“…Uptake into intact hepatocytes is rapid for both drugs (with an equilibrium between concentrations within cells and the external media being achieved within 30 s); however, because both are high clearance drugs, metabolism is substantial, even within this time period. There is considerable evidence for tissue binding of lipophilic basic drugs (Fichtl et al, 1991;Austin et al, 2005;Rodgers et al, 2005). The magnitude of accumulation of imipramine and propranolol is substantial, with concentrations being 2 orders of magnitude higher in cells than in the medium.…”

Section: Discussionmentioning

confidence: 99%

“…Lipophilic amine drugs are of particular interest for hepatic uptake, inasmuch as many have been widely reported to extensively partition into this tissue (Fichtl et al, 1991;Austin et al, 2005;Rodgers et al, 2005). The first aim of these investigations was to characterize drug uptake into isolated rat hepatocytes for two prototypic drugs, imipramine and propranolol, over a wide concentration range.…”

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confidence: 99%

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Uptake and Intracellular Binding of Lipophilic Amine Drugs by Isolated Rat Hepatocytes and Implications for Prediction of in Vivo Metabolic Clearance

Hallifax

Houston

2006

Drug Metab Dispos

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ABSTRACT:The hepatic uptake of imipramine and propranolol was investigated after incubation with isolated rat hepatocytes over a wide concentration range (0.04-400 M). The cell-to-medium concentration ratio (K p ) was concentration-dependent and could be described using a two-site binding model incorporating a high affinity/low capacity site and a linear component for a site which was apparently not saturated. Maximum (at 0.04 M) and minimum K p values (at 400 M) were 360 and 280, and 110 and 70 for imipramine and propranolol, respectively. During these incubations, metabolism was inhibited using aminobenzotriazole (an irreversible inhibitor of cytochrome P450). Pretreatment of cells either by freezethawing or with saponin (which permeabilizes the plasma membrane) eliminated the saturable process. The saturable uptake process of imipramine was also inhibited by 18 other lipophilic amine drugs (including propranolol). This uptake component may involve membrane transporter(s), whereas the nonsaturable component probably represents partition into the phospholipid component of membranes. Propranolol was further investigated to determine the impact of high K p values on hepatocellular clearance. The area under the curve for propranolol concentrations in the total incubate (medium including the cells) from the depletiontime profile was substantially greater than the corresponding area under the curve for the drug concentration in the extracellular medium, and this difference approximated the nonsaturable uptake component. It is concluded that the clearance of propranolol in isolated hepatocytes is not rate-limited by hepatic uptake and is directly proportional to unbound drug concentration, being independent of the higher K p value.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Uptake and Intracellular Binding of Lipophilic Amine Drugs by Isolated Rat Hepatocytes and Implications for Prediction of in Vivo Metabolic Clearance

Hallifax

Houston

2006

Drug Metab Dispos

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“…Because the low-affinity binding is weak and the free and bound drugs are in the fast exchange, it is reasonable to assume that the two assumptions for Langmuir isotherm are also applicable for the low-affinity binding between a drug and HSA. The binding process can be described by the equation (1) Suppose that each HSA molecule has a maximum of n sites available for accepting ligand molecules, and the total concentration of HSA and ligand in solution are C P and C L , respectively. We have the following relations:…”

Section: Resultsmentioning

confidence: 99%

NMR Study on the Low-Affinity Interaction of Human Serum Albumin with Diclofenac Sodium.

Mao

et al. 2002

Chem. Pharm. Bull.

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“…The equations (3)- (6) can easily be extended, e.g. to account for active transport processes (19,20), linear-or nonlinear metabolism (20,21), binding to other relevant molecules (20,22), including target molecules (19) and downstream effects. This opens the door for a wide range of applications in pharmacokinetics and -dynamics.…”

Section: Discussionmentioning

confidence: 99%

“…(21), or the consideration of specific tissue binding components that may be important for the specific drug of interest, e.g. (22).…”

Section: Introductionmentioning

confidence: 99%

Physiologically based pharmacokinetic modelling: a sub-compartmentalized model of tissue distribution

Kleist

Huisinga²

2007

J Pharmacokinet Pharmacodyn

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We present a sub-compartmentalized model of drug distribution in tissue that extends existing approaches based on the well-stirred tissue model. It is specified in terms of differential equations that explicitly account for the drug concentration in erythrocytes, plasma, interstitial and cellular space. Assuming, in addition, steady state drug distribution and by lumping the different sub-compartments, established models to predict tissue-plasma partition coefficients can be derived in an intriguingly simple way. This direct link is exploited to explicitly construct and parameterize the sub-compartmentalized model for moderate to strong bases, acids, neutrals and zwitterions. The derivation highlights the contributions of the different tissue constituents and provides a simple and transparent framework for the construction of novel tissue distribution models.

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Tissue Binding versus Plasma Binding of Drugs: General Principles and Pharmacokinetic Consequences

Cited by 79 publications

References 180 publications

Uptake and Intracellular Binding of Lipophilic Amine Drugs by Isolated Rat Hepatocytes and Implications for Prediction of in Vivo Metabolic Clearance

Uptake and Intracellular Binding of Lipophilic Amine Drugs by Isolated Rat Hepatocytes and Implications for Prediction of in Vivo Metabolic Clearance

NMR Study on the Low-Affinity Interaction of Human Serum Albumin with Diclofenac Sodium.

Physiologically based pharmacokinetic modelling: a sub-compartmentalized model of tissue distribution

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